Alpha-(2-thienyl) benzylureas and methods for producing the same



Patented June 2, 1953 FATE OFFICE a: 2.;- THIENYL'). LURiEASfiANDQDiET-He ODS. FOB: BRQDUCING THELSAME'S" porationzofiNemulersey NoDi'awinn. ApplicatiomAnrilifl,1950;. SferiafNo. 158,599"

wherein R stands for hydrogen; lower alkyl, or lower aliphatic carboxyliceacylizradicals. Gomepoundsrof-i the present inventicnare useful? as anticonvulsantsend.analgesics.

The simplest member of the new-class of compounds, namely, a-(2-'thienyllbenzylurea; can be prepared by reacting an Q-(Z-thienyDbenZyl amine. acid add=ition.-salt, e: g;; the' hydrocliloride', with a salt of cyanic acid, e: g".-, potassiumfcyanatev It*can alsobe prepared by reacting the ir ee base, a-(Z thienyl) benzylamine; with nitroureaa When a-(2-thienyl) benzylamine is reacted witha loweralk-yl isocyanate; e: g;, methyl isocyanate, the-reds obtained a l-lower alkylli' the(2=thieny)-- benzyllurear: The reactions ma-y beecarriedtout in the presence of any suitable diluent: By? acylating a- 2'-thienyl) b'enzylurea with aalower aliphatic carboxylic acyl halide, e. g., acetyl chloride, propionylfcliloride or -"theelik'e, tll'e presence of an acid bindir'rgagentg; ea gr, pyridinee.

chloride. To obtain the free base, the salt is reacted with an alkaline agent, e. g., sodium hydroxide. The base can be converted to any desired salt by the usual methods well known in the art.

The following example will serve to illustrate the preparation of a-(2-thienyl)benzylamine and the acid addition salts thereof.

EXAMPLE A A mixture of 110 cc. of 28 per cent ammonia and cc. of per cent formic acid was heatedto C. until the water was distilled off. To the formamide thus formed 71 grams of phenyl 2-thieny1 ketone were added. The mixture was heated for 7 hours at -190" C. until it had become homogeneous. Upon;= cooling, crystals formed. which were. filtered. and washed. with xylene. The crude N-' [d- (2-th'ienyl) b'enzyll formamide'tli'u-sdormed'was recrystallized:from 125 cc.

methanol -and Z80 ccz: oi 'waterz Upon furtherxrer crystallization fronrlxylenedt melted atc83e-84 C51.

of'r'concentrated".(37- 'perrcent) hydrochloric; acid:

was, heated ima. water bath :1 for 20: .2 minutes at 60 C. The resulting; mixturel'was. evaporatedxto: dryness and the residue wastaken up with ethanol, which was then evaporated. The final residue-=Was-dissolved irr 100cc: ofwarm methanol-and. the; resulting: solution filtered-h Upon addition.. of"; ether; to the. filtrate, crystals ofa-(Z-thienyJ).benzylamine hydrochloride formedwhich"; were filteredofi. and. washed with: ether.

Thezhydrochloride melted with decompositionat about 2253 C;

2.0;;g'rams ofa=(Zfihienybbenzylaminey hydrochloride. were-treated. with 25 cc; of water... and 10. cover. a. 40, pencentiaqueous sodium hydroxide solution... An-ioilysenarated. whichwas extracted with 55 cc-'.@of benzene... Ther-benzene-solution. was

dried over sodium sulfate and fractionallydistilled in vacuos. The. free, lea-sen, a..-2-.-thienyl):- benzylamine, was collected at l74Tl76 C./ 15 mm. as an oil of the refractive index n :1.607.

The following examples,willlserye to illustrate the preparation ofthe neww a-(2.-thienyl)benzylureas.

EXAMPLEI as (zkthienyllbenzylurewr A" filtered solution of" 3.78; grams; of (2-5 thienyDbenzylamine hydrochloride'inz ifli cc. of 50 per cent methanol "wasmixedjwith a, solution of 1.92"grams ofpotassium cyanate'in-10"cc. of

water. After heating the mixture for 15 minutes on the steam bath and cooling, the crystals which separated were filtered and washed with water. After recrystallization from 10 volumes of xylene, the a-(2-thienyl)benzy1urea thus obtained melted at 132-133 0.

EXAMPLE 2 (Z-thzenyl) benzylurea To a solution of 1.91 grams of distilled a-(Z-thienyDbenZyIamine in 5 cc. of dioxane and 1 cc. of water there was added 1.22 grams of nitrourea. A solid material formed immediately. Upon addition of 5 cc. of dioxane and 5 cc. of water, and heating for 10 minutes on the water bath, the solid material dissolved with some effervescence. Upon cooling and addition of water, a-(2-thienyl)benzylurea crystallized. It was filtered, washed with water and with Dry Ice cooled methanol. After recrystallization from 10 volumes of xylene, the compound .melted at 13l-132 C.

EXAMPLE 3 1-methyZ-3- [a- (Z-thienyl) benzyl] urea To a solution of 1 cc. of methyl isocyanate in 2 cc. of benzene there was added a solution of 1.89 grams of a-(2-thienyl)benzylamine in 20 cc.

of benzene. After refluxing the mixture for 25 minutes and cooling, the crystals which formed were filtered 01f and washed with benzene and petrol ether. The melting point of the l-methyl- 3-[a-(2-thienyl)benzyllurea thus obtained, after recrystallization from 10 volumes of toluene, was 169-170 C.

EXAMPLE 4' 1-acetyZ-3- [a- (Z-thienyl) benzyllurea A mixture of 3.21 grams of a-(2-thienyl) ben-.

zylurea, 20 cc. of pyridine and 1.1 cc. of acetyl chloride was refluxed for 45 minutes. After adding 40 grams of ice and 20 cc. of concentrated hydrochloric, crystals formed which were filtered and Washed with water and with Dry-Ice cooled methanol. After two recrystallizations from methanol, the l-acetyl-3- [a- (2-thienyl) benzyll urea thus obtained melted at 125-126 C.

EXAMPLE 5 1 -propionyZ-3- [a- (Z-thienyl) benzyl] urea A mixture of 1.16 grams of a-(2-thienyl) benzylurea, 4 cc. of pyridine and 1 cc. of propionyl chloride was refluxed for one hour. After cooling andadding cc. of water and 5 cc. of 20' per cent hydrochloric acid, crystals formed which were washed with water and with Dry-Ice cooled methanol. The crude material was recrystallized from 4 cc. of methanol. Upon a second recrystallization from 5 cc. of toluene and 12 cc. of petrol ether, the 1-propiony1-3-[a-(2-thienyl) benzyllurea thus obtained melted at Ill-113 C.

I claim:

1. A compound of the following formula:

wherein R is a member of the group consisting of hydrogen, lower alkyl, and lower aliphatic carboxylic acyl radicals.

2. a- (2-thienyl) benzylurea.

3. 1-methyl-3-[a- (2-thienyl) benzyllurea.

CHNHCONHR 4. 1-acety1-3- [a- (2-thienyl) benzyllurea.

5. 1-propionyl-3- [a- (Z-thienyl) benzyl] urea.

6. The process which comprises reacting an a-(Z-thienyDbenZyIamine acid addition salt with a salt of cyanic acid to obtain a-(2-thienyl)benzylurea.

7. The process according to claim 6, wherein a-(2-thienyl)benzylamine hydrochloride and potassium cyanate are employed in the reaction.

ROBERT DUSCHINSKY.

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Bernthsen and Sudborough: Organic Chemistry, Van Nostrand (N. Y.), 1925. (1922 Ed.), page 549.

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Richter: Organic Chemistry, Wiley, 1938, pp. I

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Williams: Detoxication Mechanisms, Wiley, N. Y., 1947, page 194. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 